Project Summary: Cardiovascular (CV) disease is the leading cause of death in the United States. Obesity greatly exacerbates the risks for adverse CV events, including myocardial infarction and sudden cardiac death. Adverse CV events cluster around 9 AM, possibly related to underlying circadian rhythms in the CV system. In healthy humans, we have discovered that the internal body clock causes notable daily changes in many CV disease risk markers, with sympatho-vagal responses to stress, prothrombotic markers, and cortisol all peaking in the vulnerable morning period. These circadian CV rhythms prepare healthy humans for anticipated rigorous activity during the day, but this circadian ?priming of the pump? could be deleterious in obese individuals already susceptible to CV disease. For example, animal studies show that obesity causes circadian disruptions, which in turn have deleterious effects on the CV system, including reduced life span, cardiomyopathy and increased ischemic infarct sizes. Nevertheless, endogenous circadian rhythms in CV risk factors have never been studied in obese humans. Thus, to determine if circadian rhythms of CV physiology may increase CV risk in obesity, our aims are: (1) to determine if obese individuals have normal or abnormal basal circadian rhythms of CV physiology, and (2) to determine if obese individuals have normal or abnormal circadian rhythms in CV reactivity to stresses. To document circadian rhythms, 28 participants (14 obese, 14 lean) will complete a 5 day in-lab protocol in dim light with behaviors scheduled evenly across the entire circadian cycle so that we can reveal strictly endogenous circadian rhythms. The important CV risk markers that we will measure include hemodynamic variables (blood pressure, heart rate, endothelial function), autonomic function (circulating epinephrine and norepinephrine, cardiac vagal tone), plus markers of prothrombotic state, oxidative stress, and inflammation. In addition, to determine how the heart adapts to the chronically increased efferent sympathetic activity in obesity, we will use short-lived positron emission tomography (PET) ligands to measure the balance between sympathetic pre-synaptic function (norepinephrine) and postsynaptic function (beta-adrenergic receptor density) in the cardiomyocytes across the circadian cycle in lean and obese individuals. We hypothesize that people with obesity will have abnormal circadian rhythms of CV risk markers including BP, vascular function and mechanistic markers of thrombosis, inflammation and oxidative stress. We also expect that the reactivity of these markers to real-life stressors such as ?getting out of bed? and mild intensity physical activity will be exaggerated in obesity at circadian phases corresponding to the morning vulnerable time. Finally, we hypothesize that chronically increased sympathetic activity in obesity will lead to down-regulation of post-synaptic beta-adrenergic receptors and mismatch between pre- and post-synaptic function, a mechanism of increased CV risk. These studies will help us elucidate circadian mechanisms of CV risk in obesity.